1. Field of the Invention
This invention relates to 5H-thioeno(3,4-c)pyrrole-4,6-dione derivatives which are active as inhibitors of tumor necrosis factor (TNF) released by cells, the preparation of these derivatives, as well as their application as pharmaceutically-active ingredients.
2. Description of the Related Art
Tumor necrosis factor-alpha (TNFα) is a cytokine, mainly produced by mononuclear macrophages. It causes inflammation, fever, cardiovascular dysfunction, hemorrhage, blood coagulation and a series of acute reactions similar to acute infection and shock when administered to humans and animals. Moreover, excessive or uncontrolled TNFα in animals or humans often indicates one of the following diseases:    1) Endotoxaemia and/or toxic shock syndrome (Tracey et al., Nature 330, 662-4 1987; Hinshaw et al., Circ Shock 30, 279-92 (1990));    2) Cachexia (Dezube et al., Laucet, 335(8690), 662 (1990)); or    3) Adult Respiratory Distress Syndrome (ARDS) (Millar et al., Laucet 2(8665), 712-714 (1989)).
At present, the disease most commonly linked to TNFα released by tumor and host tissue is hypercalcemia, which is closely related to malignant tumors (Calci. Tissue Int. (US) 46(Suppl.), S3-10 (1990)). It has also been observed that immune response is closely related to an increased concentration of TNFα in serum of the patient after bone marrow transplantation (Holler et al., Blood, 75(4), 1011-1016 (1990)).
Fatal hyperacute neurogenic syndrome brainstem-type malaria, which is the most dangerous type of malaria, is also linked to high levels of TNFα in blood. When this kind of malaria occurs, the levels of TNFα in serum are directly related to the disease, which often occurs during an acute attack of malaria in patients (Grau et al., N. Engl. J. Med. 320(24), 1586-91 (1989)).
TNFα also plays an important role in bone resorption diseases including arthritis (Betolinni et al., Nature 319, 516-8 (1986)). TNFα may stimulate bone resorption by stimulating the formation and activation of osteoclast and inhibit the formation of bone, which was shown both by in vitro and in vivo experiments.
TNFα plays an important role in chronic pneumonia, as well. The storage of silicon-containing particles can cause silicosis. Silicosis is a type of progressive respiratory failure, resulting from fibrosis of pulmonary tissues. In an animal pathological model, TNFα antibody can fully block the progress of lung fibrosis in mice caused by silica dust (Pignet et al., Nature, 344:245-7 (1990)). It was also proved that TNFα levels are abnormally high in serum of animals with pulmonary fibrosis caused by silica dust or asbestos dust in animal experiments (Bissonnette et al., Inflammation 13(3), 329-339 (1989)). Pathological research reveals that TNFα levels in pulmonary tissues of patients with pulmonary sarcoidosis is much higher than that of ordinary people (Baughman et al., J. Lab. Clin. Med. 115(1), 36-42 (1990)). This suggests that TNFα inhibitor could have a great significance in the treatment of chronic pulmonary diseases and lung injury.
One reason for inflammation occurring in the patient with reperfusion injury may be abnormal levels of TNFα.
TNFα is regarded as the chief cause inducing tissue injury caused by ischemia (Uadder et al., PNAS 87, 2643-6 (1990)).
Besides, it has been shown that TNFα may start retroviral replication including that of HIV-1 (Duh et al., Proc. Nat. Acad. Sci., 86, 5974-8 (1989)). T-cells need to be activated before HIV invades them. Once the activated T-cells are infected by virus (HIV), those T-cells must remain in an activated state in order for the HIV virus genes are able to express and/or replicate successfully. Cytokines, especially TNFα, play an important role in the process of HIV protein expression or viral replication controlled by T-cells. Inhibition of TNFα production can in turn inhibit HIV replication in T-cells (Poll et al., Proc. Nat. Acad. Sci., 87, 782-5 (1990); Monto et al., Blood 79, 2670 (1990); Poll et al., AIDS Res. Human Retrovirus, 191-197 (1992)).
cAMP can regulate many functions of cells, such as inflammation response, including asthma, and inflammation (Lome and Cheng, Drugs of the futune, 17(9), 799-807, 1992). When inflammation occurs, increased cAMP concentration in white cells inhibits activation of white cells, and then releases inflammation regulatory factors including TNFα so as to exacerbate inflammation in patients. Consequently, the inhibition of TNFα release can alleviate inflammation diseases including asthma.
Yu Yanyan et al, have found that TNFα plays an important role in the process of liver necrosis in patients with viral hepatitis. (Yu Yanyan etc., Chinese Journal of Internal Medicine 1996, 35:28-31). This shows that TNFα inhibitors may play a great role in treatment of chronic hepatic disease and liver injury.
Li Yingxu et al have found that levels of synthesis and secretion of tumor necrosis factors in monocytes in the peripheral blood of patients with chronic hepatic disease increase, which induces secretion of other cytokines (for example, IL-1β, IL-6 and IL-8). All these cytokines including tumor necrosis factors are all together involved in the injury process of hepatocytes (Journal of Qiqihar Medical Colleg, 22(10):1119-1120, 2001). Their study results coincide with the conclusions of Yoshioka, et al. (Hepatology, 1989, 10:769-777) and Wang Xin, et al. (Chinese Journal of Infectious Diseases, 1997, 15(2):85-88). It has also been found that thalidomide, the inhibitor of TNFα, is able to inhibit TNFα secretion of monocytes in the peripheral blood of hepatitis patients, which lays a foundation for the application of TNFα inhibitors to treatment of hepatitis, cirrhosis and liver cancer.
By promoting biosynthesis and release of inflammatory cytokines (Abboud H. E. Kidney Int. 1993, 43: 252-267), increasing expression of cellular adhesion molecules (Egido J. et al, Kidney Int. 1993, 43(suppl 39): 59-64), and stimulating biosynthesis and release of prostaglandin G2 (PGG2) and platelet-activating factor (PAF) (Cammusi G. et al, Kidney Int., 43(suppl 39): 32-36), TNFα may induce aggregation and adhesion of inflammatory cells, increase dilation and permeability of blood capillaries, induce fever, increase the count of neutrophilic granulocytes in blood circulation, and change hemodynamics leading to injury of renal cells. Many studies have suggested that TNFα plays an important role in breakout and deterioration of nephritis.
TNFα regulates the differentiation of B lymphocytes and reinforces the cytotoxicity of natural killer cells (NK), so as to involve in the regulation of immunel functions by means of activation of macrophages and immunological stimulation of proliferation of T-lymphocytes.
Therefore, decreasing TNFα levels and/or increasing cAMP levels constitutes an effective way to treat many inflammatory, infectious, immune or malignant tumor diseases, including but not limited to septic shock, endotoxic shock, hemodynamic shock, septic syndrom, post ischemic reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic disease, cachexia, transplant immune rejection, cancer, autoimmune disease, opportunistic infection in AIDS, rheumatoid arthritis (RA), hepatitis, nephritis, rheumatoid spondylitis, and so on. Accordingly, research and development on small molecule TNFα inhibitors with low toxicity and high efficiency is of great social benefit and has high economic value.